Heart disease is the leading death cause in the United States. Myocardial infarction (MI) affects over 80 million American people and approximately 5 million Americans are living with heart failure, which increases with an annual rate of about 500,000 new cases. Given the limited regenerative capability of heart, end stage heart failure is irreversible and heart function of MI patients cannot be spontaneously recovered. Heart transplantation is the ultimate treatment strategy for end stage heart failure patients. However, approximately 50,000 people die each year due to the limited availability of donor hearts for transplant. Heart tissue engineering offers the potential of making cardiac tissues ex vivo for future therapy of heart disease, such as for replacement of cardiac valves, myocardium implantation, drug screening, as well as engineering functional whole heart for transplantation. Heart tissue engineering requires a resource of cardiovascular cells and three dimensional (3D) scaffolds. The general strategy of engineering heart tissue is achieved by mixing functional non-human heart cells, such as beating neonatal mouse CMs and vascular cells, with biomaterial matrices. A variety of synthetic and natural derived matrices have been utilized. However, most of the synthetic matrices have biocompatibility problems and do not preserve the same 3D architectures, complex compositions and micro-niches as the extracellular matrix (ECM) in native heart, which functions to support heart formation and maintain heart function. In addition, due to the limited availability of human heart cells, human heart tissue engineering has been largely remained underdeveloped. Recently we developed a novel strategy for rebuilding human heart constructs by recellularizing whole acellular mouse hearts with multipotential cardiovascular progenitors (MCPs) derived from human induced pluripotent stem (iPS) cells. MCPs represent the earliest human heart progenitors in human cardiogenesis. When reseeded into acellular mouse hearts, MCPs in situ differentiated into cardiomyocytes (CMs), smooth muscle cells (SMCs) and endothelial cells (ECs) with high efficiency, which reconstructed the decellularized mouse hearts. The engineered heart constructs exhibited muscle and vessel-like structures, contracted spontaneously with a rate of 40-50 beats per min, exhibited intracellular Ca2+ transients and responded as expected to various drug interventions. Therefore our study established a novel strategy, which could be used to regenerate personalized human heart tissues as well as whole hearts using patient-specific iPS cells. The central aim of this proposal is to test whether human iPS cell- derived MCPs could be used to repopulate whole acellular human heart scaffolds for rebuilding whole bioartificial human hearts. In addition, we will examine the impact of human heart ECMs on CM commitment from reseeded human MCPs. Outcome of this proposal will be significant for the future translational therapy of human heart disease.